Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Authors:
Gabriel Cuellar-Partida Yi Lu Suzanne C Dixon Peter A Fasching Alexander Hein Stefanie Burghaus Matthias W Beckmann Diether Lambrechts Els Van Nieuwenhuysen Ignace Vergote Adriaan Vanderstichele Jennifer Anne Doherty Mary Anne Rossing Jenny Chang-Claude Anja Rudolph Shan Wang-Gohrke Marc T Goodman Natalia Bogdanova Thilo Dörk Matthias Dürst Peter Hillemanns Ingo B Runnebaum Natalia Antonenkova Ralf Butzow Arto Leminen Heli Nevanlinna Liisa M Pelttari Robert P Edwards Joseph L Kelley Francesmary Modugno Kirsten B Moysich Roberta B Ness Rikki Cannioto Estrid Høgdall Claus Høgdall Allan Jensen Graham G Giles Fiona Bruinsma Susanne K Kjaer Michelle A T Hildebrandt Dong Liang Karen H Lu Xifeng Wu Maria Bisogna Fanny Dao Douglas A Levine Daniel W Cramer Kathryn L Terry Shelley S Tworoger Meir Stampfer Stacey Missmer Line Bjorge Helga B Salvesen Reidun K Kopperud Katharina Bischof Katja K H Aben Lambertus A Kiemeney Leon F A G Massuger Angela Brooks-Wilson Sara H Olson Valerie McGuire Joseph H Rothstein Weiva Sieh Alice S Whittemore Linda S Cook Nhu D Le C Blake Gilks Jacek Gronwald Anna Jakubowska Jan Lubiński Tomasz Kluz Honglin Song Jonathan P Tyrer Nicolas Wentzensen Louise Brinton Britton Trabert Jolanta Lissowska John R McLaughlin Steven A Narod Catherine Phelan Hoda Anton-Culver Argyrios Ziogas Diana Eccles Ian Campbell Simon A Gayther Aleksandra Gentry-Maharaj Usha Menon Susan J Ramus Anna H Wu Agnieszka Dansonka-Mieszkowska Jolanta Kupryjanczyk Agnieszka Timorek Lukasz Szafron Julie M Cunningham Brooke L Fridley Stacey J Winham Elisa V Bandera Elizabeth M Poole Terry K Morgan Ellen L Goode Joellen M Schildkraut Celeste L Pearce Andrew Berchuck Paul D P Pharoah Penelope M Webb Georgia Chenevix-Trench Harvey A Risch Stuart MacGregor

Hum Genet 2016 07 13;135(7):741-56. Epub 2016 Apr 13.

Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

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http://dx.doi.org/10.1007/s00439-016-1663-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976079PMC
July 2016
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